Dysregulation of cholesterol homeostasis in vascular cells is a key feature in cardiovascular diseases including atherosclerosis (Sani et al., 2004). Elevated cholesterol biosynthesis in cells is attributed to high blood cholesterol, leading to an increased production of very-low density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) (Glass, et al., 2001). The accumulation of these lipoproteins, in particular LDL, is believed to induce the transformation of macrophages/vascular smooth muscle cells to foam cells through the uptake of LDL by the LDL receptor, which eventually triggers atherosclerotic plaque formation. It would be ideal to reduce LDL accumulation to ameliorate foam cell progression.
The current remedy in the treatment of high blood cholesterol is statins. Statins inhibit the HMG-CoA reductase enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis, and thus lowering the cholesterol synthesis (Shefer, et al., 1972). The intracellular biosynthetic cholesterol concentration is tightly regulated by a feedback mechanism that involves the regulation of the sterol response element transcription factor protein (SREBP) (Brown, et al., 1997). The SREBP families of proteins are basic-helix-loop-helix leucine zipper transcription factors. SREBP-1a, SREBP-1c, and SREBP-2 proteins are encoded by two distinct genes, SREBF-1 and SREBF-2 (Gasic, et al., 1994). SREBP-2 is the critical regulator of cholesterol biosynthesis through its transcriptional regulation of multiple cholesterol genes, including HMG-CoA reductase (HMGCR), farnesyl-diphosphate farnesly transferase (squalene synthase; FDFT1), and LDLR (Brown, et al., 1997; Shimomura, et al., 1997).
The underlying mechanism that regulates SREBP-2 activity is poorly understood. There is little information as to whether SREBP-2 expression may be post-transcriptionally regulated by microRNAs (miRNAs), although aberrant expression of certain miRs is suggested to be associated with cardiovascular diseases.
Accordingly, there is a continuing need to understand if there is an association between specific miRNAs and pathogenesis of lipid dysregulation. The present invention provides a novel approach of enhancing miR-185 in a cell so as to regulate SBEBP-2, thus regulating LDLR and LDL uptake as well as cholesterol synthesis in the cell. The present invention also provides the use miR-185 in predicting cardiovascular diseases in humans.